1. Milestones in Antenatal Screening Intensive Course on Screening for Down’s Syndrome Wolfson Institute of Preventive Medicine London May 2013 Jack Canick BROWN Women & Infants ’

2. Prevalence of NTDs at Birth in England and Wales 1965-1973 Adapted from: Wald NJ, Leck I. Antenatal and Neonatal Screening, Oxford, 2000 Spina bifida Anencephaly

3. BROWN Women & Infants’ Milestones in Antenatal Screening: Maternal Serum Screening for Open Neural Tube Defects YearMilestoneInvestigator(s) 1956First description of alpha-fetoproteinBergstrand and Czar 1960sExtremely high rates of NTD’s in regionsElwood of the UK 1972Raised amniotic fluid AFP and NTDsBrock and Sutcliffe 1972/3Raised serum AFP and anencephalyHino; Brock 1974Raised serum AFP and open spina bifidaWald ; Brock 1976The concept of the MoMWald 1977The specification and performance of AFPWald and screening for NTDs (the first example of aCuckle routine serum screening programme for birth defects) David Brock Univ. of Edinburgh

4. BROWN Women & Infants’ Milestones in Antenatal Screening: Maternal Serum Screening for Open Neural Tube Defects YearMilestoneInvestigator(s) 1956First description of alpha-fetoproteinBergstrand and Czar 1960sExtremely high rates of NTD’s in regionsElwood of the UK 1972Raised amniotic fluid AFP and NTDsBrock and Sutcliffe 1972/3Raised serum AFP and anencephalyHino; Brock 1974Raised serum AFP and open spina bifidaWald; Brock 1976The concept of the MoMWald 1977The specification and performance of AFPWald screening for NTDs (the first example of a and routine serum screening programme forCuckle birth defects)

5. Prevalence of NTDs at Birth in England and Wales 1965-1997 Folic acid: primary prevention of neural tube defects (Wald) Adapted from: Wald NJ, Leck I. Antenatal and Neonatal Screening, Oxford, 2000

6. John Langdon Down 1828-1896 OC Ward, John Langdon Down, A Caring Pioneer, Royal Soc Med Press, 1998 At one time, Langdon Down was on staff at the Royal London Hospital, which is now joined with Barts. Patient photographed by Langdon Down in 1865

7. BROWN Women & Infants’ Milestones in Antenatal Screening: Screening for Down’s Syndrome Using Maternal Age YearMilestoneInvestigator(s) 1933Maternal age and risk of Down’s syndromePenrose 1959Discovery of trisomy 21 in Down’s syndromeLejeune; Jacobs 1968First antenatal diagnosis of Down’s syndromeValenti 1970sAntenatal screening for Down’s syndrome 1966First chromosomal analysis from amnioticSteele and Breg fluid 1970susing maternal age: Amniocentesis offered to older women Lionel Penrose Galton Professor of Human Genetics, UCL Jerome Lejeune Université Rene Descartes, Paris Patricia Jacobs Medical Research Council, Edinburgh

8. BROWN Women & Infants’ YearMilestoneInvestigator(s) 1970sPrenatal screening for open neural tube defects using maternal serum AFP 1970sPrenatal screening for Down’s syndrome using maternal age:Amniocentesis offered to older women 1983Association of low serum AFP and fetalMerkatz chromosomal abnormalities 1984Low serum AFP and Down’s syndromeCuckle and Wald 1987Estimating the risk of Down’s syndromeCuckle and Wald pregnancy using maternal age and serum AFP to older women Milestones in Antenatal Screening: Second Trimester Serum Screening for Down’s Syndrome I Howard Cuckle Univ. of Leeds Irwin Merkatz Albert Einstein College of Medicine, NY

9. BROWN Women & Infants’ YearMilestoneInvestigator(s) 1987Elevated serum hCG & Down’s syndromeBogart 1988Low serum uE3 & Down’s syndromeCanick, Haddow,Wald 1988Serum screening for Down’s syndromeWald, Haddow, using the ‘triple test’Canick 1992Immunoreactive inhibin as a secondvan Lith trimester marker for Down’s syndrome 1996Four marker serum screening with additionWald of inhibin A Milestones in Antenatal Screening: Second Trimester Serum Screening for Down’s Syndrome II

10. BROWN Women & Infants’ Milestones in Antenatal Screening: First Trimester Screening for Down’s Syndrome YearMilestoneInvestigator(s) 1985Abnormal skin thickening of neck in fetusesBenacerraf with Down’s syndrome in the second trimester 1990Increased nuchal translucency and Down’sSzabo syndrome in the first trimester (Brohnstein 1989) 1991PAPP-A and Down’s syndrome in the firstBrambati trimester 1992Free beta-hCG and Down’s syndrome in theSpencer first trimester 1992Nuchal translucency as a screening test forNicolaides Down’s syndrome 1996Combining ultrasound and biochemicalWald markers in first trimester screening

11. Milestones in Antenatal Screening: Integrated Screening for Down’s Syndrome YearMilestoneInvestigator(s) 1999Combining first and second trimesterWald markers into a single ‘integrated’ screening test for Down’s syndrome 2000sSequential strategies for the integrated test

12. BROWN Women & Infants’ June 14, 2008, a major event in screening history: The Queen’s birthday honor list.

13. Milestones in Antenatal Screening: Fetal Nucleic Acids in the Maternal Circulation YearMilestoneInvestigator(s) 1997free fetal DNA in maternal blood Lo 2008proof of concept papers usingQuake massively parallel genomic sequencing Lo 2010-13rapidly advancing field Nov 2011clinical implementation by Sequenom

14. In the year 2013, we have many choices: The Screening Café Menu Starters 1 st trimester ultrasound ₤ 20 1 st trimester doppler ₤ 30 Main Dish 1 st trimester combined ₤ 20 2 nd trimester quad ₤ 30 Serum integrated ₤ 40 Full integrated ₤ 50 Sequential integrated ₤ 50 Desserts 2 nd trimester anomaly scan ₤ 30 Secondary DNA screening ₤400